Study about Mir15a/Mir16-1 Cluster and Its Novel Targeting Molecules Negatively Regulate Cardiac Hypertrophy | Chapter 10 | Advancement and New Understanding in Medical Science Vol. 3

In this study, we screened hypertrophic-associated miR-NAs. We demonstrate the mir15a/mir16-1 cluster is negatively correlated with the degree of cardiac hypertrophy in patients with HCM. Additionally, CCAAT/enhancer binding protein (C/EBP)  β is responsible for its down- regulation in CMs by directly binding to its promoters. In response to pathological stimuli, the heart develops ventricular hypertrophy that progressively decompensates and leads to heart failure. miRNAs are increasingly recognized as pathogenic factors, clinically relevant biomarkers, and potential therapeutic targets. We identified that mir15a/mir16-1 cluster was negatively correlated with hypertrophic severity in patients with hypertrophic cardiomyopathy. The mir15a/mir16-1 expression was enriched in cardiomyocytes (CMs), decreased in hypertrophic human hearts, and decreased in mouse hearts after transverse aortic constriction (TAC). CM-specific mir15a/mir16-1 knockout pro- moted cardiac hypertrophy and dysfunction after TAC. CCAAT/enhancer binding protein (C/EBP) β was responsible for the downregulation of mir15a/mir16- 1 cluster transcription. Mechanistically, mir15a/mir16-1 cluster attenuated the insulin/IGF1 signal transduction cascade by inhibiting multiple targets, including INSR, IGF-1R, AKT3, and serum/glucocorticoid regulated kinase 1 (SGK1). Pro-hypertrophic response induced by mir15a/mir16-1 inhibition was abolished by knockdown of insulin receptor (INSR), insulin like growth factor 1 receptor (IGF1R), AKT3, or SGK1. In vivo systemic delivery of mir15a/mir16-1 by nanoparticles inhibited the hypertrophic phenotype induced by TAC. Importantly, decreased serum mir15a/mir16-1 levels predicted the occurrence of left ventricular hypertrophy in a cohort of patients with hypertension. Therefore, mir15a/mir16-1 cluster is a promising therapeutic target and biomarker for cardiac hypertrophy. Nanoparticle-carrying mir15a/mir16-1 treatment decreases cardiac hypertrophy and improves cardiac function in an experimental animal model of pressure overload. Our study exhibits important clinical implications for both the treatment and prediction of cardiac hypertrophy.

mir15a/mir16-1 cluster exerts protective effects against the progression of the car- diac hypertrophy and dysfunction (left). During hypertrophic stress, increased C/EBP β downregulates the mir15a/mir16-1 cluster, resulting in up-regulation of multiple target proteins (INSR, IGF1R, AKT3, SGK1) in cardiomyocytes, causing increased activation of insulin/IGF1 signaling, ultimately causing car- diac hypertrophy and dysfunction. The CHO-PEGA delivery system replenishes mir15a/mir16-1 in the heart, attenuating cardiac hypertrophy and heart failure (right). Meanwhile, reduced circulating mir15a/mir16-1 levels are associated with the hypertrophic degree and cardiac hypertrophy risk in patients (bottom).

Author(s) Details:

Hongchang Guo,
Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China.

Ke Ma,
Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China.

Wenjing Hao,
Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China.

Yao Jiao,
Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China.

Ping Li,
Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China.

Jing Chen,
Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China.

Chen Xu,
State Key Laboratory of Chemical Resource Engineering, and Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, China.

Fu-jian Xu,
State Key Laboratory of Chemical Resource Engineering, and Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, China.

Wayne Bond Lau,
Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, United States.

Jie Du,
Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China.

Xin-liang Ma,
Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, United States.

Yulin Li,
Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China.

Please see the link here: https://stm.bookpi.org/ANUMS-V3/article/view/13165